Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2

Dishevelled (Dv1) is a multifunctional effector of different Wnt cascades. Both canonical Wnt3a and noncanonical Wnt5a stimulate casein-kinase-1 (CK1) -mediated phosphorylation of Dv1, visualized as electrophoretic mobility shift [phosphorylated and shifted Dv1 (ps-Dv1)]. However, the role of this phosphorylation remains obscure. Here we report the functional interaction of ps-Dv1 with the receptor tyrosine kinase Ror2, which is an alternative Wnt receptor and is able to inhibit canonical Wnt signaling. We demonstrate interaction between Ror2 and ps-Dv1 at the cell membrane after Wnt3a or Wnt5a stimulus dependent on CK1. Ps-Dv1 interacts with the C-terminal proline-serine-threonine-rich domain of Ror2, which is required for efficient inhibition of canonical Wnt signaling. We further show that the Dv1 C terminus, which seems to be exposed in ps-Dv1 and efficiently binds Ror2, is an intrinsic negative regulator of the canonical Wnt pathway downstream of beta-catenin. The Dv1 C terminus is necessary and sufficient to inhibit canonical Wnt/beta-catenin signaling, which is dependent on the presence of Ror2. Furthermore, both the Dv1 C terminus and CK1 epsilon can inhibit the Wnt5a/Ror2/ATF2 pathway in mammalian cells and Xenopus explant cultures. This suggests that phosphorylation of Dv1 triggers negative feedback regulation for different branches of Wnt signaling in a Ror2-dependent manner.-Witte, F., Bernatik, O., Kirchner, K., Masek, J., Mahl, A., Krejci, P., Mundlos, S., Schambony, A., Bryja, V., Stricker, S. Negative regulation of Wnt signaling mediated by CK1-phosphorylated Dishevelled via Ror2. FASEB J. 24, 2417-2426 (2010). www.fasebj.org